1,737 research outputs found
Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels
Macrophages are essential players in the process of fracture healing, acting by remodeling of the extracellular matrix and enabling vascularization. Whilst activated macrophages of M1-like phenotype are present in the initial pro-inflammatory phase of hours to days of fracture healing, an anti-inflammatory M2-like macrophage phenotype is supposed to be crucial for the induction of downstream cascades of healing, especially the initiation of vascularization. In a mouse-osteotomy model, we provide a comprehensive characterization of vessel (CD31+, Emcn+) and macrophage phenotypes (F4/80, CD206, CD80, Mac-2) during the process of fracture healing. To this end, we phenotype the phases of vascular regeneration-the expansion phase (d1-d7 after injury) and the remodeling phase of the endothelial network, until tissue integrity is restored (d14-d21 after injury). Vessels which appear during the bone formation process resemble type H endothelium (CD31hiEmcnhi), and are closely connected to osteoprogenitors (Runx2+, Osx+) and F4/80+ macrophages. M1-like macrophages are present in the initial phase of vascularization until day 3 post osteotomy, but they are rare during later regeneration phases. M2-like macrophages localize mainly extramedullary, and CD206+ macrophages are found to express Mac-2+ during the expansion phase. VEGFA expression is initiated by CD80+ cells, including F4/80+ macrophages, until day 3, while subsequently osteoblasts and chondrocytes are main contributors to VEGFA production at the fracture site. Using Longitudinal Intravital Microendoscopy of the Bone (LIMB) we observe changes in the motility and organization of CX3CR1+ cells, which infiltrate the injury site after an osteotomy. A transient accumulation, resulting in spatial polarization of both, endothelial cells and macrophages, in regions distal to the fracture site, is evident. Immunofluorescence histology followed by histocytometric analysis reveals that F4/80+CX3CR1+ myeloid cells precede vascularization
Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape
Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria
Quantum inelastic conductance through molecular wires
We calculate non-perturbatively the inelastic effects on the conductance
through a conjugated molecular wire-metal heterojunction, including realistic
electron-phonon coupling. We show that at sub-band-gap energies the current is
dominated by quantum coherent transport of virtual polarons through the
molecule. In this regime, the tunneling current is strongly increased relative
to the case of elastic scattering. It is essential to describe the full quantum
coherence of the polaron formation and transport in order to obtain correct
physics. Our results are generally applicable to one-dimensional atomic or
molecular wires.Comment: 4 pages, 4 figures, accepted for publication in Physical Review
Letter
Risk in CNS drug discovery: focus on treatment of Alzheimer's Disease
Despite rapid progress in our understanding of disease mechanisms and an exploding list of new targets for therapeutic intervention, drug discovery and development remains a highly risky business. Understanding the risk involved requires appreciation of the differing perspectives of risk held by the various stakeholders involved in drug research. Risk can be reduced by thoughtful management of drug candidate selection, careful planning and program execution by a team of engaged experts, and disciplined decision making. Drug development is particularly challenging for treatments of neurodegenerative diseases such as Alzheimer's disease, in which translation from animal models of efficacy to human success is poor or unknown, the timelines for clinical study are long, and the markers of efficacy are still evolving. Despite this there are several therapies in clinical development that hold the promise of influencing this disease through novel and possibly synergistic mechanisms
<Abstract of published report>Two Biflavonoids in the Farinose Exudate of Pentagramma triangularis.
<Abstract of published report>A Flavonostyilbene and Two stilbene Oligomers in Roots of Sophora leachiana.
<Abstract of published report>Three New Phenolic Compounds from the Roots of Sophora leachiana.
Electrostatic potential profiles of molecular conductors
The electrostatic potential across a short ballistic molecular conductor
depends sensitively on the geometry of its environment, and can affect its
conduction significantly by influencing its energy levels and wave functions.
We illustrate some of the issues involved by evaluating the potential profiles
for a conducting gold wire and an aromatic phenyl dithiol molecule in various
geometries. The potential profile is obtained by solving Poisson's equation
with boundary conditions set by the contact electrochemical potentials and
coupling the result self-consistently with a nonequilibrium Green's function
(NEGF) formulation of transport. The overall shape of the potential profile
(ramp vs. flat) depends on the feasibility of transverse screening of electric
fields. Accordingly, the screening is better for a thick wire, a multiwalled
nanotube or a close-packed self-assembled monolayer (SAM), in comparison to a
thin wire, a single-walled nanotube or an isolated molecular conductor. The
electrostatic potential further governs the alignment or misalignment of
intramolecular levels, which can strongly influence the molecular I-V
characteristic. An external gate voltage can modify the overall potential
profile, changing the current-voltage (I-V) characteristic from a resonant
conducting to a saturating one. The degree of saturation and gate modulation
depends on the metal-induced-gap states (MIGS) and on the electrostatic gate
control parameter set by the ratio of the gate oxide thickness to the channel
length.Comment: to be published in Phys. Rev. B 69, No.3, 0353XX (2004
<Abstract of published report>Two Flavonol Glycosides, Hexandrasides C and D, from the Underground Parts of Vancouveria hexandra.
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